Inhibition of Lin-11, Isl-1, and Mec‑3 Kinase (LIMK) Activity Attenuates Astrogliosis and Vascular Remodeling in an Experimental Model of Cuprizone-Induced Demyelination in Mice.

A variety of neurological impairments are caused by the loss of myelin, which is a hallmark of demyelinating diseases such as multiple sclerosis (MS). The cuprizone model is a well-established demyelination model in which specific brain regions undergo persistent demyelination after cuprizone administration. LIM kinases (LIMKs), a downstream of the RhoA/ROCK pathway, regulate cytoskeletal reorganization through the depolymerization of actin filaments. In our previous findings, LIMK1's phosphorylation was found to be enhanced during chronic phases of spinal cord injury (SCI), leading to scar formation and neuronal loss. However, the specific implications of the LIMK pathway on demyelination and axonal damage in nontraumatic neurodegenerative disorders remain unresolved. In this study, we explored the differential expressions of phosphorylated LIMK1 (p-LIMK1) in a cuprizone-induced acute and chronic demyelination model and its further correlation with astrogliosis and vascular remodeling. BMS-5, the LIMK inhibitor, alleviated cuprizone-induced demyelination, exerting its therapeutic effects via inhibiting LIMK expression. This resulted in the diminution of astrogliosis marked by reduced glial fibrillary acidic protein (GFAP) and neural/glial antigen 2 (NG2) expression and the subsequent maintenance of myelin integrity. Additionally, BMS-5 treatment was associated with improved motor function. Overall, these findings suggest that LIMK inhibition with BMS-5 holds promise as a therapeutic approach for demyelination.